Miltefosine induces apoptosis-like cell death in yeast via Cox9p in cytochrome c oxidase.

Abstract

Miltefosine has antifungal properties and potential for development as a therapeutic for invasive fungal infections. However, its mode of action in fungi is poorly understood. We demonstrate that miltefosine is rapidly incorporated into yeast, where it penetrates the mitochondrial inner membrane, disrupting mitochondrial membrane potential and leading to an apoptosis-like cell death. COX9, which encodes subunit VIIa of the cytochrome c oxidase (COX) complex in the electron transport chain of the mitochondrial membrane, was identified as a potential target of miltefosine from a genomic library screen of the model yeast Saccharomyces cerevisiae. When overexpressed in S. cerevisiae, COX9, but not COX7 or COX8, led to a miltefosine-resistant phenotype. The effect of miltefosine on COX activity was assessed in cells expressing different levels of COX9. Miltefosine inhibited COX activity in a dose-dependent manner in Cox9p-positive cells. This inhibition most likely contributed to the miltefosine-induced apoptosis-like cell death.

• Authors: Xiaoming Zuo, Julianne T Djordjevic, Johanes Bijosono Oei, Desmarini Desmarini, Stephen D Schibeci, Katrina A Jolliffe, Tania C Sorrell
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 80 Issue 3 Pg. 476-85 (Sep 2011) ISSN: 1521-0111 [Electronic] United States
• PMID: 21610197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• DNA Primers
• Phosphorylcholine
• miltefosine
• Electron Transport Complex IV

Topics

• Antifungal Agents (pharmacology)
• Apoptosis (drug effects)
• Base Sequence
• DNA Primers
• Electron Transport Complex IV (metabolism)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Saccharomyces cerevisiae (cytology, drug effects, enzymology)